The fluorination of bioactive molecules can have profound and unique effects on their biological and physicochemical properties, including their stability, solubility, lipophilicity, bioavailability and conformation. While as many as 20% of pharmaceutical agents and 30% of agrochemicals contain at least one fluorine atom, the tertiary alkylamine motif is similarly prevalent, found in an estimated 26% of such compounds.<sup> </sup>The combination of these ubiquitous functional groups is, therefore, a promising strategy for the development of novel biologically active molecules. In particular, a fluorine motif placed proximal to an amine exerts a significant and predictable effect on the basicity of the nitrogen atom, offering a potentially useful tactic for determining structure-activity relationships during lead optimization.<br/><br/>Despite the attractive properties offered by the β-fluoroamine motif, the application of α-(monofluoromethyl)amines in discovery chemistry is limited by a lack of synthetic accessibility. To address this problem, we report a visible light-mediated strategy that enables the construction of tertiary α-(monofluoromethyl)amines from a range of secondary amines and aldehydes, using fluoroiodomethane as a monofluoromethyl radical source. This methodology provides access to novel fluorinated amine motifs that display structural and functional features of potential value in drug discovery and agrochemical research.

Synthesis of fluorinated tertiary amines via visible light-mediated carbonyl fluoroalkylative amination

ACS Fall 2020 Virtual Meeting

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